XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results

Background:

We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer.

Methods:

NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed.

Results:

The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85–1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83–1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4.

Conclusion:

Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.     

XELOX与FOLFOX6方案一线治疗晚期结直肠癌的近期疗效及不良反应比较

目的：比较卡培他滨（希罗达）联合奥沙利铂（XELOX）方案与亚叶酸钙、5-氟尿嘧啶（5-FU）联合奥沙利铂（FOLFOX6）方案一线治疗晚期转移性结、直肠癌的疗效和不良反应。方法：将62例晚期结、直肠癌患者随机分为两组,XELOX方案组（n=31）：卡培他滨（capecitabine,Xeloda）1000mg／m^2,2次／d,口服,第1天至第14天;奥沙利铂（oxaliplatin）130mg／m^2,静脉滴注,持续3h,第1天;21天为1周期。FOLFOX6方案组（n=31）：亚叶酸钙（CF）200mg／m^2,静脉滴注,第1天,5-FU前;5-FU400mg／m^2,静脉推注,第1天,2400mg／m^2,静脉持续滴注46h;奥沙利铂100mg／m^2,静脉滴注,持续3h,第1天;14天为1周期。结果：XELOX组缓解率（RR）为48．4％,中位肿瘤进展时间（TTP）6．8个月;FOLFOX6组RR为51．6％,TTP为7．1个月;两组比较各项指标差异无统计学意义（P〉0．05）。不良反应中XELOX组手足综合征发生率高于FOLFOX组,Ⅲ、Ⅳ度中性粒细胞减少发生率低于FOLFOX6组。结论：XELOX方案一线治疗晚期结、直肠癌有确切疗效,不良反应能耐受,与FOLFOX6方案相当,但XELOX方案用药更为方便,安全性更好。     

XELOX与FOLFOX6方案一线治疗晚期结直肠癌的近期疗效及不良反应比较

目的:比较卡培他滨(希罗达)联合奥沙利铂(XELOX)方案与亚叶酸钙、5-氟尿嘧啶(5-FU)联合奥沙利铂(FOLFOX6)方案一线治疗晚期转移性结、直肠癌的疗效和不良反应.方法: 将62例晚期结、直肠癌患者随机分为两组,XELOX方案组(n=31):卡培他滨(capecitabine,Xeloda)1000mg/m2,2次/d,口服,第1天至第14天;奥沙利铂(oxaliplatin)130mg/m2,静脉滴注,持续3h,第1天;21天为1周期.FOLFOX6方案组(n=31):亚叶酸钙(CF)200mg/m2,静脉滴注,第1天,5-FU前;5-FU 400mg/m2,静脉推注,第1天,2400mg/m2,静脉持续滴注46h;奥沙利铂100mg/m2,静脉滴注,持续3h,第1天;14天为1周期. 结果: XELOX组缓解率(RR)为48.4%,中位肿瘤进展时间(TTP)6.8个月;FOLFOX6组RR为51.6%,TTP为7.1个月;两组比较各项指标差异无统计学意义(P＞0.05).不良反应中XELOX组手足综合征发生率高于FOLFOX组,Ⅲ、Ⅳ度中性粒细胞减少发生率低于FOLFOX6组.结论: XELOX 方案一线治疗晚期结、直肠癌有确切疗效,不良反应能耐受,与FOLFOX6方案相当,但XELOX方案用药更为方便,安全性更好.     

Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial

Background:

Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer.

Methods:

We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial.

Results:

Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6–4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction.

Conclusions:

Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings.     

The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer

Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine (Pounds 2132) and tegafur with uracil (Pounds 3385) were lower than costs for the intravenous Mayo regimen (Pounds 3593) and infusional regimens on the de Gramont (Pounds 6255) and Modified de Gramont (Pounds 3485) schedules over the same treatment period. Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens.     

Quality-of-life findings from a randomised phase-III study of XELOX vs FOLFOX-6 in metastatic colorectal cancer

Background:

A phase-III trial showed the non-inferiority of oral capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) in terms of efficacy in first-line treatment of metastatic colorectal cancer. A secondary objective was to compare the quality of life (QoL) and health-care satisfaction of patients.

Methods:

Patients were randomised to receive XELOX (n=156) or FOLFOX-6 (n=150) for 6 months. Quality of life and satisfaction were assessed by the Quality of Life Questionnaire-C30 (QLQ-C30) and Functional Assessment of Chronic Illness Therapy Chemotherapy Convenience and Satisfaction Questionnaire (FACIT-CCSQ), respectively. Patients completed questionnaires at baseline, at Cycle3 (C3) and Cycle (C6) (XELOX) or at C4 and C8 visits (FOLFOX-6) and at their final visit.

Results:

A total of 245 and 225 patients were assessed using QLQ-C30 and FACIT-CCSQ, respectively. The completion rates were >80%. Global QoL scores did not differ significantly between groups during the study. According to FACIT-CCSQ, XELOX seemed more convenient (C3/C4, P<0.001; C6/C8, P=0.009) and satisfactory to patients (C6/C8, P=0.003) than FOLFOX-6. At the final visit, XELOX patients spent fewer days on hospital visits (3.3 vs 5.3 days, P=0.045) and lost fewer hours of work/daily activities (10.2 vs 37.1 h lost, P=0.007).

Conclusion:

XELOX has a similar QoL profile, but seemed to be more convenient in terms of administration at certain time points and reduced time lost for work or other activities compared with FOLFOX-6.     

Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study

The surprising results published by FIRE-3 revealed that the overall survival (OS) of RAS wild-type metastatic colorectal cancer (mCRC) patients treated with Cetuximab(Cmab) and FOLFIRI combination was prolonged to 33.1 months. The substantial increase in testing and treatment costs, however, impose a considerable health burden on patients and society. Hence the study was aimed to assess the cost-effectiveness of RAS screening before monoclonal antibodies (mAbs) therapy based on FIRE-3 study. Four groups were analyzed: group 1, patients with KRAS testing treated with Cmab and FOLFIRI; group 2, patients with RAS testing treated with Cmab and FOLFIRI; group 3, patients with KRAS testing treated with bevacizumab(Bmab) and FOLFIRI; group 4, patients with RAS testing treated with Bmab and FOLFIRI. A Markov model comprising 3 health states (progression-free survival, progressive disease and death) was built. The costs were calculated from a Chinese payer perspective, and survival was reported in quality-adjusted life-months (QALMs). Average total lifetime costs ranged from $104,682.44 (RAS-Bmab) to $136,867.44 (RAS-Cmab), while the survival gained varied from 16.88 QALMs in RAS-Bmab to 21.85 QALMs in RAS-Cmab. The cost per QALM was $6,263.86 for RAS-Cmab, $6,145.84 for KRAS-Bmab, $6,201.57 for RAS-Bmab and $6,960.70 for KRAS-Cmab respectively. The KRAS-Cmab strategy was dominated by the other 3 groups. The first-treatment cost of RAS-Cmab was the most influential one to the model. In all, the RAS screening prior to Cmab treatment in mCRC seems to be a cost-effective strategy in the time of monoclonal antibodies (mAbs) therapy with the most gained QALMs.     

Cost-effectiveness of KRAS testing in metastatic colorectal cancer patients in the United States and Germany

The objective of this study was to determine the cost-effectiveness of testing for KRAS mutations before administering EGFR inhibitors such as cetuximab and panitumumab for patients with advanced metastatic colorectal cancer (mCRC) in the United States and Germany. We developed a lifetime Markov model of costs and survival associated with treating mCRC patients to assess the impact of KRAS testing before administering EGFR inhibitor-containing chemotherapy regimens. Overall, combination therapies involving cetuximab plus irinotecan/FOLFIRI had a better life expectancy (25.83 weeks) than cetuximab or panitumumab alone. Use of KRAS testing (assuming KRAS mutant patients receive only irinotecan) was equally effective and saved $12,428 per patient in the United States. When KRAS mutant patients received best supportive care, the life expectancy decreased slightly (24.26 weeks vs. 25.83 weeks) and the costs decreased by $13,501 in the United States and €9,560 in Germany. For patients treated with cetuximab alone, use of KRAS testing to identify mutations lowered costs by $8,040 per patient in the U.S. analysis and €3,856 per patient in the German analysis. For patients treated with panitumumab alone, use of KRAS testing to identify mutations lowered costs by $7,546 per patient in the U.S. analysis and €4,612 per patient in the German analysis. Model results were sensitive to the cost of chemotherapy regimens and the prevalence of KRAS mutations in the population. Under most scenarios, using KRAS testing to select patients for EGFR inhibitor therapy saved $7,500-$12,400 per patient in the United States and €3,900-€9,600 per patient in Germany with equivalent clinical outcomes.     

Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment

The treatment of colorectal cancer is rapidly becoming a significant financial burden to health-care systems within economically developed nations. A current challenge for oncologists and health-care payers is to integrate new, often high-cost, biologic therapies into clinical practice. Inherent to this process is the consideration of cost-effectiveness. The aim of this study was to compare the cost-effectiveness of cetuximab plus irinotecan with an appropriate comparator from a National Health Service (NHS) perspective. This economic evaluation is a trial-based study of cetuximab vs active/best supportive care. Effectiveness estimates for the treatment groups were modelled from key clinical trials. Cunningham et al (2004) compared cetuximab/irinotecan with cetuximab monotherapy; Cunningham et al (1998) compared irinotecan monotherapy in a second-line setting with supportive care. Modelling was necessary owing to an absence of head-to-head clinical trial data of cetuximab/irinotecan vs current standard care. Costs were calculated for the study drugs received, associated administration, palliative chemotherapy for patients in the standard care arm and other nonchemotherapy resources. The discounted life-expectancy of patients treated with cetuximab/irinotecan was 0.91 life-years, and 0.47 discounted life-years for patients receiving active/best supportive care. Patients treated with cetuximab/irinotecan accumulated mean additional costs of 18 901 pounds per patient relative to the comparator arm, with 11 802 pounds attributable to cetuximab. The incremental cost per life-year gained with cetuximab/irinotecan therapy compared with active/best supportive care was 42 975 pounds . The incremental cost per quality adjusted life-year gained was 57 608 pounds . The incremental cost per life-year gained for cetuximab/irinotecan is relatively high compared with other health-care interventions. However, this result should be considered in the context of a number of factors specific to the treated patient population.     

Systemic therapy for metastatic colorectal cancer: current questions

A proliferation of new cytotoxic and biologic agents has led to improved survival in patients with metastatic colorectal cancer (mCRC). The ability of surgery to increase long-term survival in patients with liver and/or lung metastases also has been firmly established. It has become increasingly difficult as the numbers and types of treatment options have expanded to identify optimal drug combinations, sequences, and duration and the best way to integrate systemic chemotherapy with potentially curative surgery for metastatic lesions. For this review, the authors examined how recent clinical trials have addressed some pertinent questions regarding the use of systemic chemotherapy and biologic agents in patients with mCRC.     

Capecitabine monotherapy as salvage treatment after failure of chemotherapy containing oxaliplatin and irinotecan in patients with metastatic colorectal cancer

Aim: There has been limited data on capecitabine monotherapy in metastatic colorectal cancer (CRC) patients who were previously treated with both oxaliplatin/5‐fluorouracil(FU)/leucovorin (FOLFOX) and irinotecan/5‐FU/leucovorin (FOLFIRI). Methods: We analyzed 20 patients between August 2002 and March 2008 with metastatic CRC who had been treated with capecitabine monotherapy after the failure of FOLFOX and FOLFIRI. Results: Overall, one partial response was observed (overall response rate, 5%) and stable disease was observed in 11 patients (55.0%). The disease control rate was 60.0%. The median progression‐free survival (PFS) was 2.3 months (95% CI 1.9–2.7) and the median overall survival (OS) was 5.3 months (95% CI 4.6–6.0). Patients without ascites had longer PFS than those with ascites (P = 0.02). Patients with more than three metastatic sites had poorer OS than those with less than two (P = 0.01). Grade 3 or 4 non‐hematological toxicities included hand–foot syndrome in one patient. There were no grade 3 or 4 hematological toxicities or treatment‐related deaths. Conclusion: The capecitabine monotherapy had a moderate disease control rate and a tolerable toxicity profile as third‐line or fourth‐line treatment for metastatic CRC patients who were refractory to standard chemotherapy with no further treatment options.     

Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial

Background:

Complete resection of metastases can result in cure for selected patients with metastatic colorectal cancer.

Methods:

First BEAT evaluated the safety of bevacizumab with first-line chemotherapy in 1914 patients. Prospectively collected data from 225 patients who underwent curative-intent surgery were analysed, including an exploratory comparison of resection rate in patients treated with different regimens. NO16966 compared efficacy of oxaliplatin-based chemotherapy plus bevacizumab or placebo in 1400 patients. A retrospective analysis of resection rate was undertaken.

Results:

In First BEAT, 225 out of 1914 patients (11.8%) underwent curative-intent surgery at median 64 days (range 42–100) after the last dose of bevacizumab. R0 resection was achieved in 173 out of 225 patients (76.9%). There were no surgery-related deaths and serious post-operative complications were uncommon, with grade 3/4 bleeding and wound-healing events reported in 0.4% and 1.8%, respectively. Resection rates were highest in patients receiving oxaliplatin-based combination chemotherapy (P=0.002), possibly confounded by patient selection. In NO16966, 44 out of 699 patients treated with bevacizumab (6.3%) and 34 out of 701 patients treated with placebo (4.9%) underwent R0 metastasectomy (P=0.24).

Conclusions:

The rate of serious post-operative complications in First BEAT was comparable to historical controls without bevacizumab. In NO16966, there were no statistically significant differences in resection rates or overall survival in patients treated with bevacizumab vs placebo.     

Cost-effectiveness of systemic therapies for metastatic pancreatic cancer

PurposeGemcitabine and capecitabine (gem-cap), gemcitabine and erlotinib (gem-e), and folfirinox (5-fluorouracil–leucovorin–irinotecan–oxaliplatin) are new treatment options for metastatic pancreatic cancer, but they are also more expensive and potentially more toxic than gemcitabine alone (gem). We conducted a cost-effectiveness analysis of these treatment options compared with gem.MethodsA Markov model was constructed to examine costs and outcomes of gem-cap, gem-e, folfirinox, and gem in patients with metastatic pancreatic cancer from the perspective of a government health care plan. Ontario health economic and costing data (2010 Canadian dollars) were used. Efficacy data for the treatments were obtained from the published literature. Resource utilization data were derived from a chart review of consecutive metastatic patients treated for pancreatic cancer at Princess Margaret Hospital, Toronto, Ontario, 2008–2009, and supplemented with data from the literature. Utilities were obtained by surveying medical oncologists across Canada using the EQ-5D. Incremental cost-effectiveness ratios (icers) were calculated.ResultsThe icers for gem-cap, gem-e, and folfirinox compared with gem were, respectively, CA$84,299, CA$153,631, and CA$133,184 per quality-adjusted life year (qaly). The model was driven mostly by drug acquisition costs. Given a willingness-to-pay (wtp) threshold greater than CA$130,000/qaly, folfirinox was most cost-effective treatment. When the wtp threshold was less than CA$80,000/qaly, gem alone was most cost-effective. The gem-e option was dominated by the other treatments.ConclusionsThe most cost-effective treatment for metastatic pancreatic cancer depends on the societal wtp threshold. If the societal wtp threshold were to be relatively high or if drug costs were to be substantially reduced, folfirinox might be cost-effective.     

重组人血管内皮抑制素联合化疗一线治疗晚期转移性结直肠癌的疗效观察

目的:探讨重组人血管内皮抑制素（恩度）联合化疗一线治疗晚期转移性结直肠癌的疗效及安全性。方法:60例晚期转移性结直肠癌分为试验组（n=30）和对照组（n=30）,对照组采用FOLFOX4化疗方案,试验组采用恩度联合FOLFOX4方案。结果:试验组和对照组获得的有效率（RR）分别为53.3%和36.7%（P<0.05）,疾病控制率（DCR）为83.3%和73.3%（P<0.05）,两组患者的中位无进展生存期（PFS）分别为7.3个月和5.3个月（P<0.05）,中位总生存时间（OS）分别为11.6个月和9.3个月（P<0.05）。对其中的27例肝转移患者进行亚组分析,试验组和对照组RR及DCR比较差异均有统计学意义（P<0.05）,但是PFS及OS无统计学意义（P>0.05）。主要不良反应为血液学毒性、消化道反应、神经毒性等,多为I-II级。两组患者经化疗后QOL均得到较大程度的改善;与治疗前相比,治疗后CEA和CA199均显著下降,且治疗后试验组下降较对照组更明显（P<0.05）。结论:恩度联合化疗一线治疗晚期转移性结直肠癌安全有效。     

A phase II Study of the global dose and schedule of capecitabine in Japanese patients with metastatic colorectal cancer

BACKGROUND: Although the standard 3-week capecitabine regimen (1250 mg/m(2) twice daily for 2 weeks followed by a 1-week rest) has shown superior activity and improved safety over bolus 5-fluorouracil/leucovorin in two large randomized phase III trials in Europe and in the United States, only a 4-week regimen of capecitabine (828 mg/m(2) twice daily for 3 weeks) has been studied in Japan. Therefore, we performed a phase II study to investigate the 3-week regimen of capecitabine in Japanese patients with metastatic colorectal cancer (MCRC). METHODS: Previously untreated patients with MCRC received oral capecitabine 1250 mg/m(2) twice daily for 2 weeks. Treatment was repeated every 3 weeks. Blood and urine samples were collected for pharmacokinetic analysis. RESULTS: Sixty patients were enrolled. The overall response rate was 35% [95% confidence interval (CI), 23-48%], and 52% of patients had stable disease. The median time to progression was 5.5 months (95% CI, 4.2-6.7 months). The median overall survival was 20.2 months (95% CI, 16.6-27.8 months). The most frequently occurring adverse drug reaction was hand-foot syndrome (all-grade 73%; grade 3 13%). Diarrhea, anorexia, nausea and stomatitis were each seen in 37% of patients. The pharmacokinetic profiles of capecitabine and its metabolites were similar to those reported in Caucasian patients. CONCLUSIONS: The 3-week regimen of capecitabine was effective and well tolerated in Japanese patients with MCRC as well, and could be used as the basic regimen for future combination therapies.     

氟尿嘧啶与亚叶酸钠同时连续静脉滴注联合奥沙利铂治疗转移性结直肠癌的临床观察

目的 比较同时持续静脉滴注氟尿嘧啶及亚叶酸钠联合奥沙利铂方案和改良FOLFOX6方案治疗转移性结直肠癌的疗效与毒副反应,评估亚叶酸钠代替亚叶酸钙的可行性。方法 54例晚期转移性结直肠癌患者分为亚叶酸钠组（n=30）和亚叶酸钙组（n=24）。亚叶酸钠组具体方案为：奥沙利铂85mg／m²静滴d₁,氟尿嘧啶0.4g／m2静推d1,氟尿嘧啶2.4g／m²+亚叶酸钠0.4g／m2静脉持续泵入46h;亚叶酸钙组为改良FOLFOX6方案,具体为：奥沙利铂85mg／m2静滴d1,亚叶酸钙0.4g／m²静滴d₁,氟尿嘧啶0.4g／m²静推d₁,氟尿嘧啶2.4g／m²静脉持续泵入46h。均14天为1周期,4个周期后评价疗效及毒副反应。结果亚叶酸钠组获CR 3例,PR 13例,SD 10例,有效率（RR）为53.3％,疾病控制率（DCR）86.7％;亚叶酸钙组获CR 1例,PR 11例,SD 9例,RR为50.0％,DCR为87.5％,差异无统计学意义（P＞0.05）。主要毒副反应为1～2级消化道反应、骨髓抑制和脱发,两组发生率差异均无统计学意义（P＞0.05）。结论 亚叶酸钠与氟尿嘧啶同时持续静脉滴注对结直肠癌安全、有效、方便,临床上用亚叶酸钠替代亚叶酸钙是可行的。     

XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer

The purpose of this phase II trial was to determine the efficacy and safety of the XELOX (capecitabine/oxaliplatin) regimen as first-line therapy in the elderly patients with metastatic colorectal cancer (MCRC). A total of 50 patients with MCRC aged > or = 70 years received oxaliplatin 130 mg m(-2) on day 1 followed by oral capecitabine 1000 mg m(-2) twice daily on days 1-14 every 3 weeks. Patients with creatinine clearance 30-50 ml min(-1) received a reduced dose of capecitabine (750 mg m(-2) twice daily). By intent-to-treat analysis, the overall response rate was 36% (95% CI, 28-49%), with three (6%) complete and 15 (30%) partial responses. In total, 18 patients (36%) had stable disease and 14 (28%) progressed. The median times to disease progression and overall survival were 5.8 months (95% CI, 3.9-7.8 months) and 13.2 months (95% CI, 7.6-16.9 months), respectively. Capecitabine was well tolerated: grade 3/4 adverse events were observed in 14 (28%) patients: 11 (22%) diarrhoea, eight (16%) asthenia, seven (14%) nausea/vomiting, three (6%) neutropenia, three (6%) thrombocytopenia, and two (4%) hand-foot syndrome. There was one treatment-related death from diarrhoea and sepsis. In conclusion, XELOX is well tolerated in elderly patients, with respectable efficacy and a meaningful clinical benefit response. Given its ease of administration compared with combinations of oxaliplatin with 5-FU/LV, it represents a good therapeutic option in the elderly.     

Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m(-2) twice daily) days 1-14 every 3 weeks and MMC (7 mg m(-2) IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40-77), and 23 patients (78%) were performance status 0-1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6-6.2). Median overall survival was 9.3 months (95% CI: 6.9-11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.     

Capecitabine plus oxaliplatin (XELOX) versus 5‐fluorouracil/leucovorin plus oxaliplatin (FOLFOX‐6) as first‐line treatment for metastatic colorectal cancer

A regimen consisting of 5‐fluorouracil/leucovorin plus oxaliplatin (FOLFOX‐6) is widely used in France in the first‐line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to demonstrate the non‐inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX‐6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX‐6 for 6 months. The primary endpoint was overall response rate (ORR) in the per‐protocol (PP) population; however, progression‐free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX‐6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX‐6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non‐inferiority margin of 15%. In the intent‐to‐treat population, median progression‐free survival was 8.8 months with XELOX and 9.3 months with FOLFOX‐6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX‐6 patients. We conclude that XELOX is non‐inferior in terms of efficacy to FOLFOX‐6 in the first‐line treatment of MCRC, but has a different toxicity profile.